A systems-biology model of the tumor necrosis factor (TNF) interactions with TNF receptor 1 and 2
© The Author(s) 2020. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissionsoup.com..
MOTIVATION: Clustering enables TNF receptors to stimulate intracellular signaling. The differential soluble ligand-induced clustering behavior of TNF receptor 1 (TNFR1) and TNFR2 was modeled. A structured, rule-based model implemented ligand-independent pre-ligand binding assembly domain (PLAD)-mediated homotypic low affinity interactions of unliganded and liganded TNF receptors.
RESULTS: Soluble TNF initiates TNFR1 signaling but not TNFR2 signaling despite receptor binding unless it is secondarily oligomerized. We consider high affinity binding of TNF to signaling-incompetent pre-assembled dimeric TNFR1 and TNFR2 molecules and secondary clustering of liganded dimers to signaling competent ligand-receptor clusters. Published receptor numbers, affinities and measured different activities of clustered receptors validated model simulations for a large range of receptor and ligand concentrations. Different PLAD-PLAD affinities and different activities of receptor clusters explain the observed differences in the TNF receptor stimulating activities of soluble TNF.
AVAILABILITY AND IMPLEMENTATION: All scripts and data are in manuscript and supplement at Bioinformatics online.
SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2021 |
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| Erschienen: |
2021 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:37 |
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| Enthalten in: |
Bioinformatics (Oxford, England) - 37(2021), 5 vom: 05. Mai, Seite 669-676 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Prada, Juan Pablo [VerfasserIn] |
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| Links: |
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| Themen: |
Journal Article |
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| Anmerkungen: |
Date Completed 03.06.2021 Date Revised 03.06.2021 published: Print Citation Status MEDLINE |
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| doi: |
10.1093/bioinformatics/btaa844 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM315622652 |
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| 100 | 1 | |a Prada, Juan Pablo |e verfasserin |4 aut | |
| 245 | 1 | 2 | |a A systems-biology model of the tumor necrosis factor (TNF) interactions with TNF receptor 1 and 2 |
| 264 | 1 | |c 2021 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a ƒaComputermedien |b c |2 rdamedia | ||
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| 500 | |a Date Completed 03.06.2021 | ||
| 500 | |a Date Revised 03.06.2021 | ||
| 500 | |a published: Print | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a © The Author(s) 2020. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissionsoup.com. | ||
| 520 | |a MOTIVATION: Clustering enables TNF receptors to stimulate intracellular signaling. The differential soluble ligand-induced clustering behavior of TNF receptor 1 (TNFR1) and TNFR2 was modeled. A structured, rule-based model implemented ligand-independent pre-ligand binding assembly domain (PLAD)-mediated homotypic low affinity interactions of unliganded and liganded TNF receptors | ||
| 520 | |a RESULTS: Soluble TNF initiates TNFR1 signaling but not TNFR2 signaling despite receptor binding unless it is secondarily oligomerized. We consider high affinity binding of TNF to signaling-incompetent pre-assembled dimeric TNFR1 and TNFR2 molecules and secondary clustering of liganded dimers to signaling competent ligand-receptor clusters. Published receptor numbers, affinities and measured different activities of clustered receptors validated model simulations for a large range of receptor and ligand concentrations. Different PLAD-PLAD affinities and different activities of receptor clusters explain the observed differences in the TNF receptor stimulating activities of soluble TNF | ||
| 520 | |a AVAILABILITY AND IMPLEMENTATION: All scripts and data are in manuscript and supplement at Bioinformatics online | ||
| 520 | |a SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 7 | |a Ligands |2 NLM | |
| 650 | 7 | |a Receptors, Tumor Necrosis Factor, Type I |2 NLM | |
| 650 | 7 | |a Tumor Necrosis Factor-alpha |2 NLM | |
| 700 | 1 | |a Wangorsch, Gaby |e verfasserin |4 aut | |
| 700 | 1 | |a Kucka, Kirstin |e verfasserin |4 aut | |
| 700 | 1 | |a Lang, Isabell |e verfasserin |4 aut | |
| 700 | 1 | |a Dandekar, Thomas |e verfasserin |4 aut | |
| 700 | 1 | |a Wajant, Harald |e verfasserin |4 aut | |
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| 773 | 1 | 8 | |g volume:37 |g year:2021 |g number:5 |g day:05 |g month:05 |g pages:669-676 |
| 856 | 4 | 0 | |u http://dx.doi.org/10.1093/bioinformatics/btaa844 |3 Volltext |
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